Reperfusion therapy to reopen an occluded cerebral artery is the best chance that ischemic stroke patients have of making a full recovery. Despite this less than 5% of the more than 600,000 annual patients receive the therapy. One of the main barriers to the wide spread use is the fear of the 10X increase risk of severe brain hemorrhage, which can be fatal. There is an urgent need to develop strategies to reduce this risk. It is clear that ischemia damages brain blood vessels and, in some cases, this leads to brain hemorrhage. The objective of this research is to determine why the brain bleeds upon reperfusion and to evaluate ways to provide vascular protection in an experimental stroke model. We hypothesize that both tissue-derived matrix metalloproteinases (MMPs) and blood neutrophils are necessary for the blood vessel damage that leads to hemorrhage and sometimes, worsened outcome. We plan to test this hypothesis by investigating the following two specific aims: 1) Determine the contribution of neutrophils and tissue MMPs to the disruption of microvascular integrity in the brain following temporary cerebral ischemia. 2) Evaluate the therapeutic efficacy of vascular protection strategies for temporary cerebral ischemia. These specific aims will be achieved using a rat model of reperfusion hemorrhage in which neutrophil depletion, MMP inhibition, MMP zymography and contrast-enhanced magnetic resonance imaging (MRI) will be critically evaluated to assess pathogenic mechanisms operative in the development of hemorrhage. A total of 189 animals will be studied over a three year period. At the completion of the above experiments, we expect to have a full understanding of the relative contributions of neutrophils and tissue-derived matrix proteases to the destruction of the cerebral blood vessel and the strategies that are likely to be vascular protective and contribute to improved outcome. Collectively, the successful completion of the research summarized in this proposal can be expected to contribute to the development of methods to make reperfusion safer, and therefore more accessible, to human stroke patients. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]